Computer-assisted comparisons of amino acid sequences of proteins of large DNA viruses with each other and with related cellular proteins were performed, with the emphasis on proteins that may specifically influence virus virulence. Vast collections of gene sequences of large DNA viruses are currently available, including one complete poxvirus genome and several herpesvirus genomes. The functions of a large fraction of proteins encoded by these viruses are not understood. Of particular interest are genes that are not essential for virus growth in tissue culture but influence virus virulence. A family of poxvirus proteins was described that contain two distinct domains similar to apparently unrelated cellular proteins. The N-terminal domain is related to similarly located domains of several transcription factors, and the C-terminal domain resembles a murine placental-specific protein MIPP. The latter domain consists of an array of four or five imperfect repeats. Our analysis revealed also truncated members of this protein family in poxviruses, suggesting a complex evolutionary pathway that might have involved duplications and deletions. Functions of several viral NTP-utilizing enzymes were predicted, including two poxvirus helicases and a putative NTPase that may be involved in virus maturation. A protein was identified in fowlpox virus that is related to mammalian cytidylate kinase and is proposed to possess the same enzymatic activity. A tentative phylogeny of viral and cellular thymidine and thymidylate kinases was generated and a hypothesis was developed that genes coding for enzymes of nucleotide metabolism could be acquired independently by different viruses via recombination with the respective cellular genes. A specific version of Zn finger motif was identified in a protein encoded by a gene of mousepox virus that has been sequenced in the Laboratory of Viral Diseases and has been shown to be essential for the virus to be virulent for its natural host. The comparative analysis of the Zn finger proteins of the respective family is in progress.